The serotonin (5-hydroxytryptamine, 5-HT) receptors are a group of G protein-coupled receptors (GPCRs) and ligand-gated ion channels (LGICs) found in the central and peripheral nervous systems. The 5-HT receptor family is presently delineated into seven major sub classifications, 5-HT1 family (e.g. 5-HT1A), the 5-HT2 family (e.g. 5-HT2A & 5-HT2C), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 and the interaction of serotonin with these different receptors is linked to a wide variety of physiological functions. There has been, therefore, substantial interest in developing therapeutic agents that target specific 5-HT receptor subtypes
A novel 5-hydroxytryptamine (5-HT) receptor, positively coupled with adenylate cyclase was identified in mouse embryo colliculi neurones by Dumuis and co-workers in 1988 (Dumuis et al., 1988a, b). The receptor was tentatively named 5-HT4 due to its inability to fit into the Bradley et al. (1986) classification. Since then, the 5-HT4 receptor has been officially recognized (Humphrey et al., 1993) and identified in a variety of tissues across many species (for review see Ford & Clarke, 1993). In particular, characterization of 5-HT4 receptors and identification of pharmaceutical agents that interact with them has been the focus of significant recent activity. (See, for example, the review by Langlois and Fischmeister, 5-HT4 Receptor Ligands: Applications and New Prospects J. Med. Chem. 2003, 46, 319-344.)
5-HT4 receptor modulators (e.g., agonists and antagonists) are found to be useful for the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, dyspepsia, esophagitis, gastroesophageral disease, nausea, central nervous system diseases, alzheimers disease, cognitive disorder, emesis, migraine, neurological disease, pain, and cardiovascular disorders such as cardiac failure and heart arrhythmia (Corsi. M et al., Pharmacological analysis of 5-hydroxytryptamine effects on electrically stimulated human isolated urinary bladder, Br. J. Pharmacol. 1991, 104(3), 719-725; Waikar. M. V et al., Evidence for an inhibitory 5-HT4 receptor in urinary bladder of rhesus and Cynomolgus monkeys, Br. J. Pharmacol. 1994, 111(1), 213-218; Anthony P. D. W. Ford et al., The 5-HT4 Receptor, Med. Res. Rev. 1993, 13(6), 633-662; Gary W. Gullikson et al., Gastrointestinal motility responses to the S and R enantiomers of zacopride a 5-HT4 agonist and 5-HT3 antagonist, Drug Dev. Res. 1992, 26(4), 405-417; Kaumann. A. J et al., A 5-HT4-like receptor in human right atrium, Naunyn-Schmiedeberg's Arch. Pharmacol. 1991, 344(2), 150-159).
USA patents/patent publications U.S. Pat. No. 5,726,187, U.S. Pat. No. 7,419,989, U.S. Pat. No. 7,534,889, US20060194842, US20080207690 and US20080269211 disclosed some 5-HT4 receptor compounds. While some 5-HT4 modulators have been disclosed, there continues to be a need for compounds that are useful for modulating 5-HT4. Our quest for finding novel and potent ligands as 5-HT4 receptor modulators had resulted in the discovery of 1,2-dihydro-2-oxoquinoline compounds of the formula (I) demonstrating very high 5-HT4 receptor affinity. Therefore, it is an object of this invention to provide compounds, which are useful as therapeutic agents in the treatment/prevention of a variety of disorders or disorders affected by the 5-HT4 receptor.